Amyloid Imaging and Beyond

A big boost to Alzheimer's research in recent years has come from the invention of new tracer compounds for mapping amyloid beta plaques in the brains of living people. Designed for use with positron emission tomography (PET) scanners, the new tracers are injected into the bloodstream and cross quickly into the brain, where they preferentially bind to amyloid plaques, and mark them-briefly-with emissions of mild radioactivity. Amyloid PET technology has made it easier for neurologists to diagnose difficult cases of dementia, and also has helped scientists understand how amyloid plaques accumulate during the disease process. When better drugs become available, "amyloid imaging" could enable people to begin therapy in time to avoid or greatly delay Alzheimer's dementia.

But amyloid beta plaques are just one feature of Alzheimer's. And although they build up early in the disease course, before cognitive symptoms have become evident, they are not very closely associated with the decline into dementia. "A lot of elderly people show a high density of plaques on amyloid PET scans but don't develop dementia," says Neil Vasdev of Harvard Medical School.

There are other, potentially more valuable kinds of PET tracer, not only for Alzheimer's but for other neurodegenerative diseases. Encouraged by the amyloid imaging breakthrough, scientists around the world are now racing to develop them.

Targeting tau

Already emerging from the laboratory now are PET tracers that label dysfunctional forms of the tau protein. The perceived importance of this protein in Alzheimer's has grown greatly over the past decade (See "The How of Tau"). Researchers now broadly accept that its spreading dysfunction in the brain is more closely connected to the massive loss of neurons underlying dementia, compared to the early, slow buildup of amyloid beta plaques.

However, for PET tracers, tau tangles in Alzheimer's are harder targets than plaques. Compared with the latter, the tangles are at least several times less abundant in gray matter, and they are less accessible, being found mostly within brain cells, not outside them where the plaques gather. Tau aggregates also have certain structural similarities to amyloid beta aggregates-yet any good tau tracer needs clearly to distinguish the one from the other. Despite these challenges, researchers have been making progress towards the development of tau PET tracers for almost a decade-and in the past year or so, a number of candidate tau tracers have begun to be tested in humans.

"Some of these tracers have more promising properties than others, but I think one or more will emerge and end up as a very useful agent," says Chester Mathis, a researcher at the University of Pittsburgh who co-developed the first amyloid PET tracer, PiB (Pittsburgh Compound B).

In a recent paper, as well as in conference presentations over the past year, a team from Tohoku University in Sendai, Japan, has described tests with some of their early tau tracer candidates. One of their better optimized compounds, THK-5105, labels the usual brain regions that are hit by tau pathology, and doesn't label amyloid beta deposits, in Alzheimer's brain slices as well as in living patients. THK-5015's intensity of tau-labeling in subjects' brains also tends to be higher when the subjects' cognitive test scores are lower.

Another Japanese team, from the National Institute of Radiological Sciences in Chiba, has reported similar results for their compound PBB3, which resembles plaque-binding PiB for brain-penetration purposes but is designed to bind tau instead.

A third team, from Avid Radiopharmaceuticals-developer of one of the existing amyloid plaque tracers-has described successful early tests of their new tau tracer compounds T807 and T808. In one case, a man whose brain had been imaged with T808 happened to die of unrelated causes two weeks after the test, and an autopsy of his brain confirmed the accuracy of the previous tau imaging. In another case, an unexpectedly low level of tau labeling in one dementia patient led to the discovery that the man lacked signs of amyloid plaques too, and thus had likely been misdiagnosed with Alzheimer's.

Mathis thinks it probable that tau PET tracers will start to be FDA-approved within five years. But he doubts that they can be of great use in preventing Alzheimer's dementia, given the relatively late appearance of tau pathology in the disease. "If you want to treat early in the course of the disease, and halt progression, probably you're going to have to [treat] an asymptomatic, cognitively normal subject … and amyloid beta will be the best indicator at that [early] point," he says.

Victor Villemagne, a researcher at Australia's University of Melbourne, seems more optimistic. He and his colleagues have been testing the Tohoku University tau tracer compounds in small groups of Alzheimer's and control patients. He notes that there appears to be at least a brief window of opportunity, after tau pathology becomes evident in the short-term memory region known as the hippocampus but before it spreads significantly to the long-term storage neurons of the cortex, which are considered less replaceable. "Detection at the early stages of tau deposition" thus could be medically useful, he says-when and if therapies that block Alzheimer's tau dysfunction become available.

So far, though, in the absence of any real disease-stopping treatment for Alzheimer's, medical insurers in the US seem unwilling to reimburse for routine amyloid imaging scans. That policy is likely to apply to tau scans too, says Mathis, if no therapy is available.

Other applications of tau tracers would include diagnosis to confirm or rule out Alzheimer's in cases that are hard to distinguish from other dementias; selection and monitoring of patients for drug trials; and long-term studies of the progression of tau pathology and its relation to the Alzheimer's disease process. Even in preclinical tests in mice these compounds could be valuable. Villemagne and his group, for example, have used THK tau tracers to study tau pathology in genetically-engineered mouse models of Alzheimer's. These compounds "can certainly be used to test the efficacy of anti-tau drugs," he says.

Beyond Alzheimer's

Tau is best known as an Alzheimer's disease protein, but tau dysfunction appears to drive other, less common neurodegenerative diseases as well. These "tauopathies" include chronic traumatic encephalopathy (CTE), which is thought to afflict some boxers, football players, and others who have experienced significant brain trauma; fronto-temporal dementia (Pick's disease); corticobasal degeneration syndrome; and progressive supranuclear palsy.

There are at least subtle differences between the pathological forms of tau seen in some of these tauopathies and those seen in Alzheimer's. Thus a big question for researchers now is which of these tauopathies the new tau imaging compounds will be able to image successfully. "All the data aren't in yet, but from the preliminary reports at meetings, it seems that the PBB3 compound from Japan and Avid's T807 can label a number of non-Alzheimer's tauopathies," Mathis says. He adds that the form of tau observed in CTE closely resembles that of Alzheimer's, so "my guess is that a compound that highlights Alzheimer's tau pathology will do so for CTE tau pathology as well."

Beyond tau

Parkinson's disease-associated alpha synuclein (AS) is another aggregate-forming protein that researchers and neurologists would very much like to be able to image with PET tracers. Among the efforts to develop AS-labeling tracers is one being underwritten by the Michael J. Fox Foundation, a Parkinson's research philanthropy. About two years ago, the foundation began the project by funding the screening of over 100,000 brain-penetrating compounds for AS-binding ability. Now they are funding Mathis's group and two laboratories at other universities, in an effort to develop the resulting "hits" from that screen into useful PET tracers for Parkinson's-a slow and partly treatable disease for which early diagnosis could someday be very beneficial. Mathis says that the AS tracer development effort is making good progress, although it is still a few years behind tau tracer research: "We're still at least a year or two from starting any studies in humans," he says.

Aggregate-forming proteins such as amyloid beta, tau, and alpha synuclein are not the only useful targets for PET tracers in neurodegenerative disease. Vasdev's group at Harvard Medical School, for example, has been using innovative chemistry techniques to convert existing drugs-which bind various Alzheimer's-relevant proteins in the brain-into PET tracers for diagnostic and scientific use. One of these tracers binds to a neuronal receptor type called mGluR5; another to the tau-modifying enzyme GSK-3β; another to a protein marker of Alzheimer's-linked brain inflammation; yet another to metal ions found in amyloid plaques.

PET tracer development has been ongoing since the 1970s, but most PET brain scans target basic indicators of metabolic activity such as glucose or oxygen, or brain-cell receptors for dopamine or other common neurotransmitters. Vasdev emphasizes that for neurodegenerative disease applications, there are many other targets for which PET tracers would be useful, but have not yet been developed. "There's still a lot to do in this field," he says.